tbuckley/cabot-search huggingface dataset:
Abstract GS114: Maladaptive Myeloid Lipid Metabolism Promotes Cardiac Diastolic Dysfunction Through Splenic Hematopoiesis
Authors: Mallory Filipp, Zhi-Dong Ge, Sanjiv J Shah, Edward B Thorp
Journal: Circulation Research (2022)

Rationale: Diastolic dysfunction, including during heart failure with preserved ejection fraction (HFpEF), is a widespread morbidity with limited therapeutic options. Though heterogeneous in etiology, major risk factors include hyperlipidemia, hypertension, and elevated inflammation. Inflammatory macrophages have been implicated in the promotion of diastolic dysfunction; however underlying mechanistic insight remains in its infancy. Objective: We set out to define the heterogeneity of the cardiac immune response during diastolic dysfunction to identify cell and molecular protagonists relevant to HFpEF. We hypothesized that systemic metabolic perturbations during HFpEF were promoting cardiac inflammation and fibrosis. Methods and Results: Diastolic dysfunction was induced by a combination of high fat diet (HFD) and iNOS inhibition (L-NAME). scRNAseq of the myocardium revealed significant alterations in the composition of cardiac macrophage subsets. Gene ontology analyses depicted a specific induction of pro-fibrotic and lipid handling pathways, including the fatty acid receptor Cd36. In live animals, myeloid deficiency of Cd36 prevented diastolic dysfunction and was associated with dampened cardiac inflammation. When investigating immune cell sourcing during HFpEF, it was found that a splenic hematopoietic niche formed in wild-type mice. Within splenic macrophages, HFpEF-associated risk factors activated mitochondrial metabolism, as well as expression of vascular cell adhesion molecule-1 (VCAM-1), the latter which has been shown to retain hematopoietic stem cells in the spleen. In vitro treatment of splenic macrophages with high fat was sufficient to induce expression of Vcam1, an effect found to be mediated by mitochondrial reactive oxygen species activation of the transcription factor Spic. Conclusions: Our data suggest a critical role for myeloid metabolism in the sourcing of detrimental-monocyte-derived macrophages from the spleen, to the heart.
Abstract P2015: Metabolic-epigenetic Coupling In High Fat Diet And Heart Failure With Reduced Ejection Fraction
Authors: Tatiana Gromova, Todd H Kimball, Shuxun Ren, Yibin Wang, Douglas J Chapski, Thomas M Vondriska
Journal: Circulation Research (2022)

Given rising obesity rates, understanding how metabolic changes exacerbate other cardiovascular disease (CVD) risk factors will yield novel therapeutic targets for associated comorbidities, such as heart failure. We hypothesize that obesity-related metabolic syndrome induces transcriptional programs that engender cardiac pathology via mechanisms involving chromatin regulators, thereby perpetuating the pathology by epigenetic memory. C57BL/6J adult male mice were put on a high fat diet (HFD) for 24 weeks. After HFD, hearts were in hypertrophy, as defined by an increase in heart weight to tibia length ratio (24.67 ± 5.14 mg/mm in HFD versus 17.06 ± 0.98 mg/mm in regular chow controls, p=0.026). Examination of blood plasma revealed significant increase in LDL-C (74.37 ± 22.45 mg/dL in HFD versus 21.91 ± 5.98 mg/dL in controls, p=0.0005) and insulin (452.81 ± 224.77 uIU/mL in HFD versus 89.66 ± 45.60 uIU/mL in controls, p=0.0003), indicative of metabolic disorder. RNA-seq of isolated cardiomyocytes revealed distinct transcriptomic changes at 1 week, 6 weeks, and 24 weeks of HFD. At 1 week, HFD stimulus induced promotion of lipid metabolism ( Pdk4, Per2 ) and suppression of genes related to development and proliferation ( Sox4, Epha4 ). By 6 weeks, the cardiomyocytes underwent metabolic reprogramming (downregulation of Lpl and Irs2 ) and structural changes ( Acta2, Col8a1). At 24 weeks, we observed suppression of ketolytic machinery (downregulation of Abat, Bdh1, and Oxct1 ) in response to obesity-driven hyperglycemia, suggesting that cardiomyocytes transitioned to a pre-diabetic state. To test whether this metabolic disease state compounds with other CVD risk factors, we devised a two-hit model, where mice were fed HFD for 6 weeks and then underwent transverse aortic constriction as a model of pressure overload. Cardiomyocytes from this two-hit model exhibited an enhanced hypertrophic response ( Myh7, Nppa, Col1a1 mRNA levels) compared to pressure overload with regular chow, sham surgery with HFD, or sham surgery with chow. Thus, phenotypic and transcriptional data suggest that HFD reprograms cardiomyocytes to a pre-diabetic state characterized by insulin resistance which exacerbates the effects of other CVD risk factors like hypertrophy.
Abstract P3010: Angptl4 Reduces Atherosclerosis And Promotes Fibrous Cap Stability By Targeting Klf4 In Vascular Smooth Muscle Cells
Authors: Yong-sook Kim, Dong-im Cho, Hyang H Cho, Meeyoung Cho, Young Keun Ahn
Journal: Circulation Research (2022)

Background: Atherosclerosis is vascular disease of chronic inflammation, and we recently showed that angiopoietin-like 4 (ANGPTL4) promote cardiac repair by suppressing pathological inflammation. Given the contribution of inflammation to atherosclerosis, we assessed the effect of ANGPTL4 on atherosclerosis development. Methods: We injected recombinant ANGPTL4 protein or PBS to atherosclerotic Apoe-/- mice twice a week fed a high-fat diet for 8 weeks, and analyzed atherosclerotic lesion size, inflammation, and plaque stability. The effect of ANGPTL4 on vascular smooth muscle cells (VSMCs) was studied, and plasma levels of ANGPTL4 in patients were measured. Results: ANGPTL4 treatment reduced the atherosclerotic plaque size and vascular inflammation. In the atherosclerotic lesions, the number of α-SMA(+)MYH11(+) cells was higher, while the number of CD68(+)cells was lower in the ANGPTL4 group than in the vehicle-treated group. Moreover, α-SMA-expressing fibrous cap was significantly thicker in the ANGPTL4 group than in the PBS group. Then, we isolated VSMCs from atherosclerotic aortas, and found that CD68 and Krüppel-like factor 4 (KLF4) were significantly upregulated in the PBS group. As KLF4 is a phenotypic modulator and an inducer of NADP oxidase 1 (Nox1) in VSMCs, the effect of ANGPTL4 on VSMCs was assessed. Cholesterol-induced upregulations of Nox1 and KLF4 were substantially inhibited by ANGPTL4 treatment. Then, we analyzed the circulating ANGPTL4 levels of the cardiovascular disease patients, and found the positive correlation between high ANGPTL4 and low incidence of vascular events. Conclusions: Our results showed that ANGPTL4 inhibited atherogenesis by increasing the fibrous cap thickness. KLF4 and Nox1 were suggested as targets of ANGPTL4 in VSMCs to confer plaque stability by attenuating phenotypic changes of VSMCs toward inflammatory macrophage-like cells. Taken together, circulating ANGPTL4 may be associated with regulation of vascular events.
Abstract P2093: Immunodominant Human Leukocyte Antigen-ii-restricted Epitopes In Human Apolipoprotein B
Authors: Payel Roy, John Sidney, Coleen A McNamara, Alessandro Sette, Klaus Ley
Journal: Circulation Research (2022)

Introduction: CD4 + T cell responses to apolipoprotein B are well characterized in atherosclerotic mice and also detectable in humans. CD4 + T cells recognize peptides displayed on highly polymorphic Human Leukocyte Antigen-II molecules. Immunogenicity of individual APOB peptides is largely unknown in humans. Only one HLA-II-restricted epitope was validated using a DRB1*07:01-APOB 3036-3050 tetramer. We reasoned that the T cell epitope repertoire of APOB is broader and may contain dominant antigenic regions. Hypothesis: Human APOB harbors discrete immunodominant sequences that are targeted by autoreactive CD4 + T cells in majority of donors. These trigger atherosclerosis-related autoimmune responses in humans. Objective: To optimize a restimulation-based workflow to examine antigenicity of multiple candidate peptides in HLA-typed donors, to chart TCR specificities and phenotypes of APOB-reactive cells and to profile T helper cytokine responses to APOB epitopes. Methods and Results: We selected twenty APOB peptides (APOB 20 ) from an in silico screen and validated peptide binding to the most commonly occurring HLA-II alleles. Using stringent controls, we confirmed specificity of expansion-based protocols to detect CD4 + T cytokine responses to APOB 20 pool. Ex vivo assessment of activation-induced markers revealed statistically significant autoimmune response to APOB 20 , but not to a ubiquitously-expressed negative control protein, actin. CD4 + T responses to the APOB 20 pool were resolved to the level of individual peptides using an IFNγ enzyme-linked immune-absorbent spot (ELISpot) assay. This led to the discovery of six immunodominant epitopes (APOB 6 ) that triggered robust T cell responses in most donors. High-throughput sequencing identified unique APOB 6 -specific expanded TCR clonotypes. Responding CD4 + T cells were enriched in antigen-experienced memory phenotypes. APOB 6 induced secretion of both pro-inflammatory and regulatory cytokines. In matched clinical samples, APOB 6 stimulation detected heightened expression of activation and memory markers and augmented secretion of proinflammatory cytokines in patients with more severe coronary artery disease. Conclusions: Using &gt;60 donors expressing diverse HLA-II alleles and distributed over a screening and a validation cohort of healthy subjects and a clinical cohort of CAD patients, we discovered six immunodominant APOB epitopes that allowed interrogation of dynamic antigen-specific CD4 + T responses associated with human atherosclerosis.
Importance of the time interval between FEV1 measurements in a methacholine provocation test
Authors: P Malmberg, K Larsson, BM Sundblad, W Zhiping
Journal: European Respiratory Journal (1993)

We examined the hypothesis that a forced expiratory volume in one second (FEV1) manoeuvre (and the preceding deep inhalation) before inhalation of methacholine might influence FEV1 measured after methacholine, if the time between measurements was short. Six to nine healthy subjects inhaled a single dose of methacholine, known to cause about 20% decrease in FEV1, on different days in different test protocols. If an FEV1 manoeuvre was performed immediately before methacholine, the first FEV1 measured 3 min after provocation was higher (77% of basal FEV1) than if a pre-methacholine FEV1 manoeuvre was not performed (64%). This effect of a pre-methacholine FEV1 manoeuvre was also demonstrated at 2, 4 and 6, but not at 10 min after the start of methacholine inhalation. If an FEV1 manoeuvre was not performed before methacholine, the second and subsequent FEV1 measured in constricted airways was higher than the first, and of similar magnitude to the first FEV1 in tests where a pre-challenge FEV1 manoeuvre was performed. In another trial, 10 healthy subjects performed two stepwise methacholine tests, with either 6 or 3 min between dose steps. The percentage decrease in FEV1 per mg of inhaled methacholine decreased from 2.6 (1.9-5.2) to 1.7 (0.8-2.3) (median, interquartile-range) when the time interval was shortened. The results suggest that the deep inhalation associated with the FEV1 manoeuvre decreases the bronchial tone in airways constricted by methacholine for up to 6 min, possibly due to yielding of cross-links in airway smooth muscles.
Artifacts in Dual-Energy Chest Radiography
Authors: A. Yu. Vasil’ev, D. I. Naumova
Journal: Radiology - Practice (2022)

The aim of this research is to analyze artifacts in dual-energy chest radiography: their appearance and how to eliminate them. A total of 252 patients were examined in random order by using dual-energy radiography. As a result, 756 images were analyzed. This review describes the most important and most prevalent of them, including motion artifacts - 58 (41,4%), quantum noise – 55 (39,2%) and decreasing the suppression of bony elements on soft-tissue-selective images – 27 (19,3%). The main reason of dual-energy chest radiography artifacts is incorrect image reconstruction parameters.
Abstract P3079: Hypoxia Stimulates Neonatal Hypoxia-inducible Factor 1α Dependent Macrophage Secretion Of Cardiomyocyte Mitogens
Authors: Amanda C Becker, Connor Lantz, Edward B Thorp
Journal: Circulation Research (2022)

Background: The neonatal murine heart can regenerate after injury. This regenerative capacity is dependent on macrophages and lost shortly after birth. How macrophages facilitate regeneration remains vague, and the neonatal myeloid response to hypoxia as well as the role of myeloid Hypoxia-Inducible Factors (HIFs) in cardiac regeneration are unknown. We hypothesized that post-ischemic regulation of regenerative programs are confined to neonatal cardiac macrophages and are lost in the adult. We also hypothesized hypoxia is a stimulus for neonatal macrophages to secrete cardiomyocyte mitogens in a HIF dependent manner. Methods: Single-cell sequencing was performed on cardiac myeloid cells post myocardial infarction (MI) in wildtype neonatal and adult mice to explore differences in regenerative vs reparative responses to injury. Neonatal cardiomyocytes harvested from wildtype mice were co-cultured with supernatant from hypoxia stimulated neonatal bone marrow-derived macrophages from myeloid HIF-1 α expressing vs HIF-1 α genetically depleted mice. Immunofluorescent staining with antibodies to Troponin T, Ki67, and DAPI was performed to quantify cardiomyocyte proliferation. Results: High-resolution clustering identified 3 distinct macrophage populations present in neonatal and adult mice post MI. Gene Ontology identified significantly upregulated genes in biological pathways associated with regeneration and HIF-1α stabilization in Timd4+Mrc1+ macrophages in the neonate but not the adult. Immunofluorescent staining of neonatal cardiomyocytes at steady state revealed an average of 6.0% Ki67+ cardiomyocytes compared to 35.4% Ki67+ cardiomyocytes exposed to supernatant from hypoxia stimulated HIF-1 α + macrophages (N=10/group; SEM + 1.96; p value &lt;0.0001) and 10.1% Ki67+ cardiomyocytes exposed to supernatant from hypoxia stimulated HIF-1 α - macrophages (N=10/group; SEM + 1.54; p value 0.0162). Conclusions: We have newly identified enrichment of regenerative and HIF-1α stabilization pathways specific to neonatal resident cardiac macrophages after ischemic injury. We also newly conclude hypoxia is a stimulus for neonatal macrophages to secrete HIF-1 α dependent mitogenic factors that induce cardiomyocyte proliferation.
Abstract P2016: Gut Microbiota-derived Short-chain Fatty Acids Benefit Cardiac Extracellular Matrix Remodeling In Pressure Overload
Authors: Chen-Ju Lin, Yu-Che Cheng, Hung-Chih Chen, Yu-Kai Chao, Martin Nicholson, Eric Yen, Timothy Kamp, Patrick C Hsieh
Journal: Circulation Research (2022)

Introduction: The gut microbiota has been implicated in various heart diseases by producing metabolites that modulate host immunity and metabolism. In our previous study, we found that mice with dysbiosis suffered more from cardiac rupture, resulting in higher mortality than mice possessing commensal gut flora after myocardial infarction. This suggests that there are unexplored routes to cardiovascular health through the gut microbiota. Hypothesis: We hypothesize that a community of symbiotic gut microbiota is required for heart mechanical modifications during adaptive cardiac remodeling under stress. Methods and Results: Pressure-overload stress was induced by a transverse aortic constriction (TAC) surgery and dysbiosis was induced by antibiotic treatment (ABX) in mice. Under echocardiography, ABX-TAC mice showed worse cardiac outcomes versus controls (ejection fraction = 59% ± 2% vs 67% ± 2%, P &lt; 0.001, N ≥ 12/group). Under microscopic examination of the extracellular matrix and tensile tests, ABX-TAC mice had larger fibrotic areas (9.4% ± 0.4% vs 5.7% ± 0.4%, P &lt; 0.0001) and collagen disarray, accompanied by more severe ventricular stiffening (Young’s moduli = 360 ± 10 kPa vs 280 ± 43 kPa, P &lt; 0.01, N ≥ 6/group). When establishing normal gut flora before surgery, germ-free mice had heart malfunctioning rescued (change of myocardial performance index = 15% ± 13% vs 120% ± 32% untreated, P &lt; 0.05, N ≥ 5/group). The normal gut flora was profiled by third-generation 16S sequencing to acquire bacterial information with high accuracy, followed by PICRUSt analysis revealing that the microbes favored the production of short-chain fatty acids (SCFAs) (N ≥ 8/group). When supplemented with SCFA before surgery, ABX mice gained better cardiac outcomes (ejection fraction = 65% ± 2% vs 53% ± 3% untreated, P &lt; 0.01, N ≥ 5/group). Cardiac fibroblasts treated with SCFA were less susceptible to TGF-β1-triggered fibrogenesis (COL1A1/GAPDH = 0.8 ± 0.3 vs 2.3 ± 0.3 untreated, P &lt; 0.01, n ≥ 4/group). Conclusions: In conclusion, our study demonstrates firstly that gut microbiota-derived SCFAs manipulate heart mechanical functioning under stress potentially acting via cardiac fibroblasts. This provides new insights into the management of heart diseases through the gut microbiota.
Abstract P1054: Oral Administration Of New Agonist Of Adenosine Receptor Reduces Inflammatory Process And Cardiac Remodeling Induced By Myocardial Infarction In Rats
Authors: Bianca Nascimento-Carlos, Jaqueline S Da Silva, Bruna Rocha, Tadeu Montagnoli, Rodolfo Maia, Eliezer J Barreiro, Gisele Zapata-Sudo
Journal: Circulation Research (2022)

Treatment of acute myocardial infarction (AMI) is based on strategies to relief pain and increase survival. Thus, this work investigates the effects of a new agonist of adenosine receptor called LASSBio-1860 in an experimental model of AMI, in order to improve cardiac function. The protocols were approved by the Ethics Committee for the Use of Animals at Federal University of Rio de Janeiro (# 103/17). The experimental AMI was induced by the ligation of the anterior descending coronary artery in male Wistar rats (180-200 g), which were randomly divided into groups treated orally with vehicle (DMSO) or 70 μmol/kg of LASSBio-1860 for 7 days. At the end of the experimental protocol, hemodynamic parameters were obtained using echocardiography and the expression of markers involved in the inflammatory pathway (TNF-alpha, p38) and cardiac remodeling (p-ERK-1/2 and t-ERK) was evaluated. AMI increased the left ventricular (LV) wall thickness from 0.11 ± 0.04 to 0.29 ± 0.02 cm (p &lt;0.05) which was reduced to 0.21 ± 0.01 cm after treatment with LASSBio-1860. The impaired ejection fraction observed after AMI (reduction from 91.5 ± 0.5 to 45.2 ± 1.3%) was partially reversed to 60.1 ± 10.3% with the treatment. Additionally, the agonist of adenosine receptor normalized the increased filling pressure of 31.3 ± 4.4 to 15.9 ± 3.9. Increased LV final systolic pressure was detected after AMI, changing from 83.8 ± 12.5 (control group) to 104.7 ± 1.1, which was recovered to 95.3 ± 21.4 mmHg with LASSBio-1860. An increase in the TNF-alpha expression as well as nuclear p38 labeling was detected in the heart from infarcted animals which was reduced after administration of LASSBio-1860. Furthermore, AMI increased the ratio of phosphorylated and total ERK-1/2 from 0.78 ± 0.01 to 0.89 ± 0.01 while treatment with LASSBio-1860 reduced to 0.79 ± 0.01 (p &lt; 0.05). Similarly, p38 increased from 0.72 ± 0.11 to 1.58 ± 0.36 induced by AMI but was reduced to 1.17 ± 0.43 by LASSBio-1860. An increase in collagen deposition from 3.6 ± 0.9 to 31.5 ± 4.29 was observed in hearts from infarcted animals, which was reduced to 26.8 ± 1.6 with treatment. Also, AMI promoted an increase in p38 nuclear labeling from 9.9 ± 3.9 to 40.8 ± 3.3 which was decreased to 29.9 ± 1.7 in treated animals. Similar increase and recovery was detected with iNOS because AMI caused an increase from 9.0 ± 4.1 to 25.3 ± 3.9 and improvement to 14.2 ± 0.6. In conclusion, the reduction of the inflammatory response may be related to the activation of adenosine receptors by LASSBio-1860, which leads to an improvement in AMI-induced cardiac remodeling and dysfunction.
Accuracy and reproducibility of the Assess peak flow meter
Authors: CP van Schayck, E Dompeling, C van Weel, H Folgering, HJ van den Hoogen
Journal: European Respiratory Journal (1990)

The variability of peak flow measurements was studied in 24 patients with airway obstruction, using 12 Assess peak flow meters and a Fleisch pneumotachograph type 4 as a standard. The Assess peak flow meter gave systematic under-readings of 19-34% (low accuracy). The value scale of the Assess peak flow meter should be adjusted. As systematic under-readings do not influence the variability in peak flow measurements, variability was only caused by the random error of the instrument. The random error of the Assess peak flow meter was relatively low: about 4% of the measured peak flow value (high precision). The contribution of the Assess peak flow meter to the total variability of peak flow measurements showed a linear relationship (r = 0.53) with the value of the peak flow rate itself and varied from 9% (at 3 l.s-1) to 86% (at 10.8 l.s-1). Reading errors of the peak flow meter were responsible for about 1% of the total variability. The remaining variability is probably caused by the correctness of the peak flow performance and the motivation of the patient.
Abstract P2097: Hypochloremia Alters Cardiac Physiology After Myocardial Ischemia-Reperfusion Injury
Authors: Shridhar Sanghvi, Divya Sridharan, Vincenzo Trovato, Sakima Smith, Mahmood Khan, Harpreet Singh
Journal: Circulation Research (2022)

Ischemic heart disease (IHD) is one of the leading causes of death related due to heart failure (HF). It is mainly characterized by impairment of heart contraction-relaxation (rhythmicity) and cardiac output. While a myriad of cellular processes is associated with IHD, one of the major cellular aspects strongly associated is the electrolyte and ionic imbalance. Serum sodium levels have been a well-established adverse prognostic marker for patients with chronic heart failure. Recent evidences have suggested that the lower serum chloride (hypochloremia, &amp;lt90mM) is associated with increased mortality risk in patients with chronic HF independent of serum sodium levels. Serum chloride (Cl - ) is a major anion in physiology but its correlation to IHD has not been studied extensively. Hence, to better understand the role of hypochloremia in HF patients, we reviewed patients who received a left ventricular assist device (LVAD) placement at The Ohio State University Medical Center. Survival analysis demonstrated that patients with hypochloremia before LVAD placement had decreased survival at one year compared to patients with normal serum Cl - (p=0.0055). Moreover, our e x vivo studies with isolated rat hearts indicate hypochloremia aggravates myocardial infarction post ischemia-reperfusion (IR) injury. Hence, to elucidate Cl - mediated signaling mechanism we incorporated highly translational human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Our cellular studies demonstrate that physiological alteration of extracellular Cl - affects the function of beating hiPSC-CM. Hypochloremia significantly increases the beating rate by reducing the calcium cycling durations in hiPSC-CM. Studies are ongoing to determine the involvement of the chloride channel in maintaining chloride homeostasis. Taken together, our results for the first time establish the novel role and mechanism of chloride homeostasis in IR injury. These results will advance the need to search for effective therapeutic approaches to target novel Cl - channels in IHD.